4-Aminopiperidine derivatives, processes for their preparation and their use as medicaments

ABSTRACT

4-Aminopiperidine derivatives, pharmaceutical compositions containing the same, and methods for their preparation are provided herein for the treatment of disorders of the central and/or peripheral nervous systems. In particular, the potent antidepressant activity shown by the disclosed 4-aminopiperidine derivatives are particularly useful for the prevention and/or the treatment of depression, severe depression with anxiety, anxiety disorders and affective disorders.

The present invention relates to 4-aminopiperidine derivatives, toprocesses for their preparation, to their use in therapy and topharmaceutical compositions containing them. More particularly thesecompounds are useful for treatment of disorders of the central and/orperipheral nervous system. Of particular interest is the potentantidepressant activity shown by these compounds.

Therefore, these 4-aminopiperidine derivatives are particularly usefulfor the prevention and/or the treatment of depression, severe depressionwith anxiety, anxiety disorders and affective disorders.

Depression is reported to affect up to 10% of the population, with alifetime prevalence of 19% and is linked with a significant mortality.The traditional treatment approach of depression with tricyclicantidepressants has experienced a decreased popularity since theintroduction of drugs that specifically targeted the brain serotoninsystem, namely specific serotonin reuptake inhibitors (SSRIs)represented by the widely used fluoxetine. If it is true that SSRIs haveimproved side effects compared to tricyclics, data is accumulatingshowing that this category of drugs insufficiently covers the symptomsof anxiety and insomnia which are an inherent part of depression.Moreover, these substances may, by themselves, induce nervousness,insomnia and anxiety. Thus a substantial number of patients requireco-administration of anxiolytic/hypnotic medication such asbenzodiazepines or antihistamines. The latter compounds, particularlyhydroxyzine, might be more suited than benzodiazepines inco-administration with SSRIs. Another important side effect of SSRIs issexual dysfunction that seems to be mediated by serotonin 5-HT2receptors.

Therefore, to avoid polytherapy, one chemical entity that possesses theefficacy of SSRIs and have added properties that could relievenervousness, anxiety and sexual dysfunction could be of a high benefitto the patient. In particular, such a molecule should have importantaffinities towards serotonin reuptake sites (main mode of action ofSSRIs); histamine H1 receptors to improve nervousness, anxiety andfacilitate sleep; and serotonin 5-HM2 receptors, the blockade of whichis expected to prevent sexual side effects.

Our research efforts in this field have led us to discover moleculespossessing these 3 properties, i.e inhibition of serotonin reuptakesites, blockade of histaminergic H1 receptors and blockade of serotonin5-HT2 receptors.

Recent pharmacological studies conducted by the applicant have revealedunrecognised and potent pharmacological properties of the hereinmentioned novel 4-aminopiperidine derivatives of formula (I), whichsuggest that they may be useful in treating disorders such as thosementioned above, but not limited to them.

U.S. Pat. No. 5,461,066 describes 4-aminopiperidine derivatives assynthesis intermediates. The abstract of the Japanese patent applicationJP 05148234 describes the two following compounds,N-[(4-chlorophenyl)methyl]-N-phenyl-4-piperidinamine,N-phenyl-N-(phenylmethyl)-4-piperidinamine, as having antihistaminic andanti-allergic activity.

According to one aspect therefore, the present invention provides4-aminopiperidine derivatives of formula I, including pharmaceuticallyacceptable salts thereof,

wherein R¹, R², R³, R⁴ independently are selected from hydrogen,fluorine, chlorine, methyl and trifluoromethyl, with the proviso that,if R¹, R² and R⁴ are hydrogen, then R³ is not hydrogen or halogen.

Preferred compounds according to the invention are compounds of formulaI wherein:

-   R² is hydrogen, fluorine or methyl,-   R⁴ is hydrogen, fluorine, chlorine or trifluoromethyl,-   R¹ and R³ having the same definitions as described above, with the    proviso that, if R¹, R² and R⁴ are hydrogen, then R³ is not hydrogen    or halogen,    or a pharmaceutically acceptable salt thereof.

More preferred compounds according to the invention are compounds offormula I wherein:

-   R¹ is hydrogen, fluorine or chlorine,-   R² is hydrogen, fluorine or methyl,-   R³ is hydrogen, fluorine, chlorine or methyl,-   R⁴ is hydrogen, fluorine or chlorine.-   with the proviso that, if R¹, R² and R⁴ are hydrogen, then R³ is not    hydrogen or halogen,    or a pharmaceutically acceptable salt thereof.

Most preferred compounds according to the invention are compounds offormula I wherein:

-   R¹ is hydrogen or fluorine,-   R² is hydrogen or fluorine,-   R³ is fluorine or methyl,-   R⁴ is hydrogen,-   with the proviso that, if R¹, R² and R⁴ are hydrogen, then R³ is not    fluorine,    or a pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are:

-   N-phenyl-N-[3-(trifluoromethyl)benzyl]-4-piperidinamine;    N-(3-chlorobenzyl)-N-phenyl-4-piperidinamine;    N-(3,4-difluorobenzyl)-N-phenyl-4-piperidinamine;    N-(3,4-dichlorobenzyl)-N-phenyl-4-piperidinamine;    N-(4-methylbenzyl)-N-phenyl-4-piperidinamine;    N-phenyl-N-[4-(trifluoromethyl)benzyl]-4-piperidinamine;    N-(3-chlorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine;    N-(3,4-difluorobenzyl)-N-(3-fluorophenyl) -4-piperidinamine;    N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine;    N-(4-chlorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine;    N-(3,4-dichlorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine;    N-(3-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine;    N-(3-fluorophenyl)-N-[4-(trifluoromethyl)benzyl]-4-piperidinamine;    N-(3-chlorobenzyl)-N-(3-methylphenyl)-4-piperidinamine;    N-(3,4-difluorobenzyl)-N-(3-methylphenyl)-4-piperidinamine;    N-(4-fluorobenzyl)-N-(3-methylphenyl)-4-piperidinamine;    N-(4-chlorobenzyl)-N-(3-methylphenyl)-4-piperidinamine;    N-(3,4-dichlorobenzyl)-N-(3-methylphenyl)-4-piperidinamine;    N-(3-methylphenyl)-N-[4-(trifluoromethyl)benzyl]-4-piperidinamine;    N-benzyl-N-(4-fluorophenyl)-4-piperidinamine;    N-(4-fluorophenyl)-N-[3-(trifluoromethyl)benzyl]-4-piperidinamine;    N-(3-chlorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(3,4-difluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(4-fluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(4-chlorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(3,4-dichlorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(4-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine;    N-(4-fluorophenyl)-N-[4-(trifluoromethyl)benzyl]-4-piperidinamine;    N-(4-chlorophenyl)-N-(4-fluorobenzyl)-4-piperidinamine;    N-(3-chlorobenzyl)-N-(4-methylphenyl)-4-piperidinamine;    N-(3,4-difluorobenzyl)-N-(4-methylphenyl)-4-piperidinamine;    N-(4-fluorobenzyl)-N-(4-methylphenyl)-4-piperidinamine;    N-(4-chlorobenzyl)-N-(4-methylphenyl)-4-piperidinamine;    N-(3,4-dichlorobenzyl)-N-(4-methylphenyl)-4-piperidinamine;    N-(4-methylphenyl)-N-[4-(trifluoromethyl)benzyl]-4-piperidinamine;    N-(4-fluorobenzyl)-N-[4-(trifluoromethyl)phenyl]-4-piperidinamine or    pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are:

-   N-(3-chlorobenzyl)-N-phenyl-4-piperidinamine; N-(3,4-difluorobenzyl)    -N-phenyl-4-piperidinamine;    N-(4-methylbenzyl)-N-phenyl-4-piperidinamine;    N-(3-chlorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine;    N-(3,4-difluorobenzyl)-N-(3-fluorophenyl) -4-piperidinamine;    N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine;    N-(4-chlorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine;    N-(3-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine;    N-(4-fluorobenzyl)-N-(3-methylphenyl)-4-piperidinamine;    N-benzyl-N-(4-fluorophenyl)-4-piperidinamine;    N-(3,4-difluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(4-fluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(4-chlorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(4-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine;    N-(4-chlorophenyl)-N-(4-fluorobenzyl)-4-piperidinamine or    pharmaceutically acceptable salts thereof.

Most preferred compounds of the invention are:

-   N-(4-methylbenzyl)-N-phenyl-4-piperidinamine;    N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine;    N-(3-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine;    N-(4-fluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;    N-(4-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine or    pharmaceutically acceptable salts thereof.

The best results have been obtained withN-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine andN-(3-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine, orpharmaceutically acceptable salts thereof.

The “pharmaceutically acceptable salts” according to the inventioninclude therapeutically active, non-toxic acid salt forms which thecompounds of formula I are able to form. The acid addition salt form ofa compound of formula I that occurs in its free form as a base can beobtained by treating the free base with an appropriate acid such as aninorganic acid, for example, a hydrohalic such as hydrochloric orhydrobromic, sulfuric, nitric, phosphoric and the like; or an organicacid, such as, for example, acetic, hydroxyacetic, propanoic, lactic,pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

The present invention concerns also processes for preparing thecompounds of formula I.

The compounds of formula I according to the invention can be preparedanalogously to conventional methods as understood by the person skilledin the art of synthetic organic chemistry.

The following process description sets forth certain synthesis routes inan illustrative manner. Other alternative and/or analogous methods willbe readily apparent to those skilled in this art.

According to one embodiment, compounds having the general formula I maybe prepared by the protection of a compound of formula II according tothe equation:

wherein P is a protecting group, R¹, R², R³ and R⁴ having the samedefinitions as described above.

The protecting group P may be any suitable amine protecting group suchas, for example, carbamate, sulfenyl derivatives, sulfonyl derivatives,alkyl and aryl. Non-limiting examples are methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl(Fmoc), 9-(2-sulfo)fluorenylmethoxycarbonyl,9-(2,7-dibromo)fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl(Troc), 2-phenylethoxycarbonyl, 2-chloroethoxycarbonyl,benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzenesulfenyl,2-nitrobenzenesulfenyl, tosyl, benzenesulfonyl, methyl, tert-butyl,allyl, benzyl, bis(4-methoxyphenyl)methyl or 2,4-dinitrophenyl. For moredetails concerning deprotection methods, see “Protective Groups inOrganic Chemistry”, Chapter 2, J. F. W. Omie, Plenum Press, London andNew York, 1973 and “Protective Groups in Organic Synthesis”, Chapter 7,Th. W. Greene, John Wiley & Sons, 1999.

This transformation may be carried out according to any procedure knownto the person skilled in the art.

Compounds of formula II may be prepared by reaction of a compound offormula III with a compound of formula IV according to the equation

wherein X is an halogen atom, preferably bromine, P, R¹, R², R³ and R⁴having the same definitions as described above.

This transformation may be carried out in an inert solvent, for exampleacetonitrile or dimethylformamide, in the presence of an organic or aninorganic base, for example triethylamine or potassium carbonate,between 50 and 100° C.

Compounds of formula IV are commercially available.

Compounds of formula III may be prepared by reaction of a compound offormula V with a ketone of formula VI according to the equation

This transformation may be carried out in an alcoholic solvent, forexample methanol, in the presence of 1 to 2 equivalents of an acid, forexample acetic acid, and in the presence of 1 to 2 equivalents of areductive agent such as sodium cyanoborohydride.

Compounds of formula V and compounds of formula VI are commerciallyavailable.

In another aspect, the invention provides 4-aminopiperidine derivativesof formula (I) including the pharmaceutically acceptable salts thereoffor their use as medicament.

It has finally been found that compounds of formula (I) and thepharmaceutically acceptable salts thereof are particularly effectiveantidepressant agents.

Therefore, these compounds are particularly useful for the preventionand/or the treatment of depression and severe depression with anxiety.

These compounds may also be used for the prevention and/or the treatmentof other neurological disorders including anxiety disorders,particularly generalized anxiety disorder (GAD), panic disorder (PD),post traumatic stress disorder (PTSD), social anxiety disorder (SAD),obsessive compulsive disorder and agoraphobia, bipolar disorders, mania,chronic pain, neuropathic pain, migraine, cerebral ischemia, cardiacarrhythmia, myotonia, cocaine and alcohol abuse, stroke, myoclonus,tremor, neonatal cerebral haemorrage, amyotrophic lateral sclerosis(ALS), spasticity, Parkinson's disease, and other neurodegenerative andmovement disorders.

Thus, the present invention in a further aspect concerns the use ofcompounds of formula (I) or the pharmaceutically acceptable saltsthereof as defined above, for the manufacture of a medicament for thetreatment and/or prophylaxis of neurological disorders such as mentionedabove.

In particular, the present invention concerns the use of compounds offormula (I) and the pharmaceutically acceptable salts thereof as definedabove, for the manufacture of a medicament for the treatment and/orprophylaxis of depression.

The present invention also concerns a method for treating depression, ina mammal in need of such treatment, comprising administering atherapeutic dose of at least one compound of formula (I) and thepharmaceutically acceptable salts thereof to a patient.

The methods of the invention comprise administration to a mammal(preferably human) suffering from above mentioned diseases of apharmaceutical composition according to the invention in an amountsufficient to alleviate the condition. The compound is convenientlyadministered in any suitable unit dosage form, including but not limitedto one containing 0.5 to 500 mg, preferably 1 to 100 mg of activeingredient per unit dosage form.

The term “treatment” as used by the Applicant means curative treatmentand prophylactic treatment.

By “curative” we mean the efficaciousness of formula (I) in treating thecurrent episode of depressive phase.

By “prophylactic” or “maintenance” we mean the prevention of therecurrence of depressive episodes.

For treating diseases, compounds of formula (I) or theirpharmaceutically acceptable salts may be employed at an effective dailydosage and administered via a pharmaceutical composition.

Therefore, another embodiment of the present invention is apharmaceutical composition that includes an effective amount of acompound of formula (I) or its pharmaceutically acceptable salts or aderivative in combination with a pharmaceutically acceptable carrier forany of the disorders described herein.

To prepare the pharmaceutical composition of this invention, one or moreof the compounds of formula (I), or their pharmaceutically acceptablesalts, are intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administrating, e.g., oral, rectal, or parenteral.

The present invention requires administration of an effective dose ofthe compounds for the treatment and/or the prophylaxis of diseases. Thedose required in accordance with the invention should be sufficientlyhigh to permit the relief of diseases. Pharmaceutical compositionscomprising compounds can, for example, be administered orally orparenterally, i.e., intravenously, intramuscularly or subcutaneously,intrathecally.

Pharmaceutical compositions which can be used for oral administrationcan be solids or liquids and can, for example, be in the form oftablets, pills, dragees, gelatin capsules, solutions, syrups, and thelike.

To this end, compounds can be used mixed with an inert diluent or anon-toxic pharmaceutically acceptable vehicle such as starch or lactose,for example. Optionally, these pharmaceutical compositions can alsocontain a binder such as microcrystalline cellulose, gum tragacanth orgelatine, a disintegrant such as alginic acid, a lubricant such asmagnesium stearate, a glidant such as colloidal silicon dioxide, asweetener such as sucrose or saccharin, or colouring agents or aflavouring agent such as peppermint or methyl salicylate.

They also comprise compositions which can release the active substancein a controlled manner. Pharmaceutical compositions which can be usedfor parenteral administration are in the pharmaceutical forms which areknown for this mode of administration and are in the form of aqueous oroily solutions or suspensions generally contained in ampoules,disposable syringes, glass or plastics vials or infusion containers.

In addition to the active compound, these solutions or suspensions canoptionally also contain a sterile diluent such as water for injection, aphysiological saline solution, oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents, antibacterial agents suchas benzyl alcohol, antioxidants such as ascorbic acid or sodiumbisulphite, chelating agents such as ethylene diamine-tetra-acetic acid,buffers such as acetates, citrates or phosphates and agents foradjusting the osmolarity, such as sodium chloride or dextrose.

These pharmaceutical forms are prepared using methods which areroutinely used by pharmacists.

The percentage of compound of formula (I) in the pharmaceuticalcompositions can fall within a wide range of concentrations and dependson a variety of factors such as the patient's sex, age, weight andmedical condition, as well as on the method of administration. Thus thequantity of compound of formula (I) in compositions for oraladministration is at least 0.5% by weight and can be up to 80% by weightwith respect to the composition weight, etc.).

In another embodiment, the present invention concerns also the synthesisintermediates of formula II, or III, wherein the substituents R and theprotecting group P are defined as above.

The preferred compounds of formula II are tert-butyl4-[3-fluoro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate; tert-butyl4-{[3-(trifluoromethyl)benzyl]anilino}-1-piperidinecarboxylate;tert-butyl 4-[(3-chlorobenzyl)anilino]-1-piperidinecarboxylate;tert-butyl 4-[(3,4-difluorobenzyl)anilino]-1-piperidinecarboxylate;tert-butyl 4-[(3,4-dichlorobenzyl)anilino]-1-piperidinecarboxylate;

-   tert-butyl 4-[(4-methylbenzyl)anilino]-1-piperidinecarboxylate;    tert-butyl    4-{[4-(trifluoromethyl)benzyl]anilino}-1-piperidinecarboxylate;    tert-butyl    4-[(3,4-difluorobenzyl)-3-fluoroanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(4-chlorobenzyl)-3-fluoroanilino]-1piperidinecarboxylate;    tert-butyl    4-[(3,4-dichlorobenzyl)-3-fluoroanilino]-1piperidinecarboxylate;    tert-butyl    4-[3-fluoro(4-methylbenzyl)anilino-1-piperidinecarboxylate;    tert-butyl 4-( 3-fluoro[4-(trifluoromethyl)benzyl)    anilino]-1-piperidinecarboxylate; tert-butyl    4-[(3-chlorobenzyl)-3-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(3,4-difluorobenzyl)-3-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(4-fluorobenzyl)-3-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(4-chlorobenzyl)-3-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(3,4-dichlorobenzyl)-3-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-{3-methyl[4-(trifluoromethyl)benzyl]anilino}-1-piperidinecarboxylate;    tert-butyl 4-(benzyl-4-fluoroanilino)-1-piperidinecarboxylate;-   tert-butyl    4-{4-fluoro[3-(trifluoromethyl)benzyl]anilino}-1-piperidinecarboxylate;    tert-butyl    4-[(3-chlorobenzyl)-4-fluoroanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(3,4-difluorobenzyl)-4-fluoroanilino]-1-piperidinecarboxylate;    tert-butyl    4-[4-fluoro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate;    tert-butyl    4-[(4-chlorobenzyl)-4-fluoroanilino]-1piperidinecarboxylate;    tert-butyl    4-[(3,4-dichlorobenzyl)-4-fluoroanilino]-1piperidinecarboxylate;    tert-butyl    4-[4-fluoro(4-methylbenzyl)anilino]-1-piperidinecarboxylate;    tert-butyl    4-{4-fluoro[4-(trifluoromethyl)benzyl]anilino}-1-piperidinecarboxylate;    tert-butyl    4-[4-chloro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate;    tert-butyl    4-[(3-chlorobenzyl)-4-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(3,4-difluorobenzyl)-4-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(4-fluorobenzyl)-4-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(4-chlorobenzyl)-4-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-[(3,4-dichlorobenzyl)-4-methylanilino]-1-piperidinecarboxylate;    tert-butyl    4-{4-methyl[4-(trifluoromethyl)benzyl]anilino}-1-piperidinecarboxylate;    tert-butyl    4-[(4-fluorobenzyl)-4-(trifluoromethyl)anilino]-1-piperidinecarboxylate    and tert-butyl    4-[(3-chlorobenzyl)-3-fluoroanilino]-1-piperidinecarboxylate.

The preferred compounds of formula III are tert-butyl4-(3-fluoroanilino)-1-piperidinecarboxylate; tert-butyl4-(3-toluidino)-1-piperidinecarboxylate; tert-butyl4-(4-toluidino)-1-piperidinecarboxylate.

The following examples are provided for illustrative purposes only andare not intended, nor should they be construed, as limiting theinvention in any manner. Those skilled in the art will appreciate thatroutine variations and modifications of the following examples can bemade without exceeding the spirit or scope of the invention.

Unless otherwise specified in the examples, characterisation of thecompounds was performed according to the following methods:

NMR spectra are recorded on a BRUKER AC 250 Fourier Transform NMRSpectrometer fitted with an Aspect 3000 computer and a 5 mm ¹H/¹³C dualprobe head or BRUKER DRX 400 FT NMR fitted with a SG Indigo² computerand a 5 mm inverse geometry ¹H/¹³C/¹⁵N triple probe head. The compoundis studied in DMSO-d₆ (or CDCl₃) solution at a probe temperature of 313K and at concentrations ranging from 2 to 20 mg/ml. The instrument islocked on the deuterium signal of DMSO-d₆ (or CDCl₃). Chemical shiftsare given in ppm downfield from TMS taken as internal standard. DMSO-d₆(deuterated dimethyl sulfoxide).

Mass spectrometric measurements in LC/MS mode are performed as follows:

HPLC Conditions

Analyses are performed using a WATERS Alliance HPLC system mounted withan INERTSIL ODS 3-, DP 5 μm, 250×4.6 mm column.

The gradient runs from 100% solvent A (acetonitrile, water, TFA(10/90/0.1, v/v/v)) to 100% solvent B (acetonitrile, water, TFA(90/10/0.1, v/v/v)) in 7 min with a hold at 100% B of 4 min. The flowrate is set at 2.5 ml/min and a split of 1/10 is used just before APIsource. The chromatography is carried out at 30° C.

MS Conditions

Samples are dissolved in acetonitrile/water, 70/30, v/v at theconcentration of about 250 μg/ml. API spectra (+ or −) are performedusing a FINNIGAN (San Jose, Calif., USA) LCQ ion trap mass spectrometer.APCI source operates at 450° C. and the capillary heater at 160° C. ESIsource operates at 3.5 kV and the capillary heater at 210° C.

Mass spectrometric measurements in EI/DIP mode are performed as follows:samples are vaporized by heating the probe from 50° C. to 250° C. in 5min. EI (Electron Impact) spectra are recorded using a FINNIGAN (SanJose, Calif., USA) TSQ 700 tandem quadrupole mass spectrometer. Thesource temperature is set at 150° C.

Mass spectrometric measurements on a TSQ 700 tandem quadrupole massspectrometer (Finnigan MAT, San Jose, Calif., USA) in GC/MS mode areperformed with a gas chromatograph model 3400 (Varian, Walnut Creek,Calif., USA) fitted with a split/splitless injector and a DB-5MSfused-silica column (15 m×0.25 mm I.D., 1 μm) from J&W Scientific(Folsom, Calif., USA). Helium (purity 99.999%) is used as carrier gas.The injector (CTC A200S autosampler) and the transfer line operate at290 and 250° C., respectively. Sample (1 μl) is injected in splitlessmode and the oven temperature is programmed as follows: 50° C. for 5min., increasing to 280° C. (23° C./min) and holding for 10 min. The TSQ700 spectrometer operates in electron impact (En or chemical ionization(CI/CH4) mode (mass range 33-800, scan time 1.00 sec). The sourcetemperature is set at 150° C.

Water content is determined using a Metrohm microcoulometric KarlFischer titrator.

Preparative chromatographic separations are performed on silicagel 60Merck, particle size 15-40 μm, reference 1.15111.9025, using in-housemodified Jobin Yvon-type axial compression columns (80 mm i.d.), flowrates between 70 and 150 ml/min. Amount of silicagel and solvent miresare as described in individual procedures.

Melting points are determined on a Büchi 535 Totoli-type fusionometre,and are not corrected, or by the onset temperature on a Perkin Elmer DSC7.

Unless specified otherwise in the examples, the compounds are obtainedin the neutral form.

EXAMPLE 1 Synthesis of Compounds of Formula I

1.1 Synthesis of tert-butyl 4-(3-fluoroanilino)-1-piperidinecarboxylate1

3-fluoroaniline (40 g) was dissolved in MeOH and the solution was cooledto 0° C. Tert-butyl 4-oxo-1-piperidinecarboxylate (79 g, 1.1 eq), aceticacid (26.8 ml, 1.3 eq) and sodium cyanoborohydride (29 g, 1.3 eq,portionwise) were added successively to the solution. The reactionmixture was stirred at room temperature until completion. The reactionmixture was then cooled to 0° C. and an aqueous solution of NaOH (20%)was poured into the mixture (pH˜10). The precipitate was filtered off,washed with water, dried and recrystallised from iPrOH to givetert-butyl 4-(3-fluoroanilino)-1-piperidinecarboxylate 1 (68.5 g).

Yield: 63%.

MS (MH⁺): 295.

Compounds of formula m listed in table 1 can be synthesized in ananalogous way.

TABLE 1 compounds of formula III. MH⁺ n^(°) IUPAC Name (LC − MS) 1tert-butyl 4-(3-fluoroanilino)-1-piperidinecarboxylate 295 2 tert-butyl4-anilino-1-piperidinecarboxylate 277 4 tert-butyl4-(4-fluoroanilino)-1-piperidinecarboxylate 295 5 tert-butyl4-(4-chloroanilino)-1-piperidinecarboxylate 311-313 7 tert-butyl4-[4-(trifluoromethyl)anilino]-1- 344 (MH·⁺, piperidinecarboxylate GC −MS)

1.2 Synthesis of tert-butyl4-[3-fluoro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate 8

Tert-butyl 4-(3-fluoroanilino)-1-piperidinecarboxylate 1 (20 g) wasdissolved in acetonitrile (250 ml). Potassium carbonate (33.2 g) and1-(bromomethyl)-4-fluorobenzene (11 ml) were added to the solution. Thereaction mixture was heated at reflux overnight, then cooled,concentrated and the residue was taken up in dichloromethane and water.The aqueous layer was washed twice with dichloromethane. The combinedorganic layers were dried over MgSO₄ and concentrated. The resultingwhite solid was triturated in hexane and filtered off to affordtert-butyl 4-[3-fluoro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate 8(25.5 g).

Yield: 89%.

MS (MH⁺): 403

Compounds of formula II listed in table 2 can be synthesized in ananalogous way.

TABLE II compounds of formula II. MH⁺ n^(°) IUPAC Name (LC/MS)  8tert-butyl 4-[3-fluoro(4-fluorobenzyl)anilino] 403-1-piperidinecarboxylate 10 tert-butyl4-[(3-chlorobenzyl)anilino]-1-piper- 401/403 idinecarboxylate 11tert-butyl 4-[(3,4-difluorobenzyl)anilino]-1-piperidinecar- 403 boxylate13 tert-butyl 4-[(4-methylbenzyl)anilino]-1-piperidinecar- 381 boxylate14 tert-butyl 4-{[4-(trifluoromethyl)benzyl]anilino}1- 435piperidinecarboxylate 15 tert-butyl4-[(3,4-difluorobenzyl)-3-fluoroanilino]-1- 421 piperidinecarboxylate 16tert-butyl 4-[(4-chlorobenzyl)-3-fluoroanilino]-1-piperi- 419/421dinecarboxylate 18 tert-butyl4-[3-fluoro(4-methylbenzyl)anilino]-1-piperi 399 dinecarboxylate 26tert-butyl 4-(benzyl-4-fluoroanilino)-1-piperidinecar- 385 boxylate 28tert-butyl 4-[(3-chlorobenzyl)-4-fluoroanilino]-1-piperi- 419/421dinecarboxylate 29 tert-butyl4-[(3,4-difluorobenzyl)-4-fluoroanilino]-1- 421 piperidinecarboxylate 30tert-butyl 4-[4-fluoro(4-fluorobenzyl)anilino]-1-piperi- 403dinecarboxylate 31 tert-butyl4-[(4-chlorobenzyl)-4-fluoroanilino]-1-piperi- 419/421 dinecarboxylate34 tert-butyl 4-{4-fluoro[4-(trifluoromethyl)benzyl]anilino} 453-1-piperidinecarboxylate

1.3 Synthesis of N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine43

Tert-butyl 4-[3-fluoro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate 8(25.5 g) was dissolved in dichloromethane and the solution was cooled to0° C. TFA (30 ml) was added to the solution and the reaction mixture wasstirred at room temperature. After 1 h 30, TFA (20 ml) was added and thereaction mixture was stirred for a further 30 minutes. The solvent wasremoved under vacuum and the residue was taken up in dichloromethane andwater. The aqueous phase was alkalized by addition of NaOH and washedwith dichloromethane. The combined organic layers were dried over MgSO₄and concentrated. The crude was purified by chromatography (eluant:CH₂Cl₂/MeOH/NH₄OH 95/5/0.5) to giveN-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine (18.4 g) as afree base.

A solution of ether saturated with HCl was added toN-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine dissolved inether. The precipitate was filtered off, washed with ether and dried inan oven (50° C.) under vacuum to afford 17.51 g ofN-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine 43 (2 HCl, 0.5H₂O) as a white solid.

Yield: 72%.

MS (MH⁺): 303

Compounds of formula I listed in table 3 can be synthesized in ananalogous way.

TABLE 3 compounds of formula I. n° Salt IUPAC Name MH⁺(LC − MS) 43 2HCl, 0.5 H₂O N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine 30344 2 CF₃COOH N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine 30345 2 CF₃COOH N-phenyl-N-[3-(trifluoromethyl)benzyl]-4- 335piperidinamine 46 2 HCl, 0.5 H₂ON-(3-chlorobenzyl)-N-phenyl-4-piperidinamine 301 47 2 CF₃COOHN-(3-chlorobenzyl)-N-phenyl-4-piperidinamine 301 48 2 HCl, 0.5 H₂ON-(3,4-difluorobenzyl)-N-phenyl-4-piperidinamine 303 49 2 CF₃COOHN-(3,4-difluorobenzyl)-N-phenyl-4-piperidinamine 303 50 2 CF₃COOHN-(3,4-dichlorobenzyl)-N-phenyl-4-piperidinamine 335/337/339 51 2 HCl, 1H₂O N-(4-methylbenzyl)-N-phenyl-4-piperidinamine 281 52 2 CF₃COOHN-(4-methylbenzyl)-N-phenyl-4-piperidinamine 281 53 2 HCl, 1 H₂ON-phenyl-N-[4-(trifluoromethyl)benzyl]-4- 335 piperidinamine 54 2CF₃COOH N-phenyl-N-[4-(trifluoromethyl)benzyl]-4- 335 piperidinamine 552 CF₃COOH N-(3-chlorobenzyl)-N-(3-fluorophenyl)-4- 319/321piperidinamine 56 2 CF₃COOH N-(3,4-difluorobenzyl)-N-(3-fluorophenyl)-4-321 piperidinamine 57 2 HCl, 0.5 H₂ON-(3,4-difluorobenzyl)-N-(3-fluorophenyl)-4- 321 piperidinamine 58 2CF₃COOH N-(4-chlorobenzyl)-N-(3-fluorophenyl)-4- 319/321 piperidinamine59 2 CF₃COOH N-(3,4-dichlorobenzyl)-N-(3-fluorophenyl)-4- 353piperidinamine 60 2 HCl, 0.5 H₂ON-(3-fluorophenyl)-N-(4-methylbenzyl)-4- 299 piperidinamine 61 2 CF₃COOHN-(3-fluorophenyl)-N-[4-(trifluoromethyl)benzyl]-4- 353 piperidinamine62 2 CF₃COOH N-(3-chlorobenzyl)-N-(3-methylphenyl)-4- 315/317piperidinamine 63 2 CF₃COOH N-(3,4-difluorobenzyl)-N-(3-methylphenyl)-4-317 piperidinamine 64 2 CF₃COOH N-(4-fluorobenzyl)-N-(3-methylphenyl)-4-299 piperidinamine 65 2 CF₃COOH N-(4-chlorobenzyl)-N-(3-methylphenyl)-4-315 piperidinamine 66 2 CF₃COOHN-(3,4-dichlorobenzyl)-N-(3-methylphenyl)-4- 349/351/353 piperidinamine67 2 CF₃COOH N-(3-methylphenyl)-N-[4-(trifluoromethyl)benzyl]-4- 349piperidinamine 68 2 HCl, 1 H₂ON-benzyl-N-(4-fluorophenyl)-4-piperidinamine 285 69 2 CF₃COOHN-benzyl-N-(4-fluorophenyl)-4-piperidinamine 285 70 2 CF₃COOHN-(4-fluorophenyl)-N-[3-(trifluoromethyl)benzyl]-4- 353 piperidinamine71 2 HCl, 0.5 H₂O N-(3-chlorobenzyl)-N-(4-fluorophenyl)-4- 319piperidinamine 72 2 CF₃COOH N-(3-chlorobenzyl)-N-(4-fluorophenyl)-4- 319piperidinamine 73 2 HCl, 0.5 H₂ON-(3,4-difluorobenzyl)-N-(4-fluorophenyl)-4- 321 piperidinamine 74 2CF₃COOH N-(3,4-difluorobenzyl)-N-(4-fluorophenyl)-4- 321 piperidinamine75 2 HCl, 0.5 H₂O N-(4-fluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine303 76 2 CF₃COOH N-(4-fluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine303 77 2 HCl N-(4-fluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine 30378 2 HCl, 0.5 H₂O N-(4-chlorobenzyl)-N-(4-fluorophenyl)-4- 319piperidinamine 79 2 CF₃COOH N-(4-chlorobenzyl)-N-(4-fluorophenyl)-4- 319piperidinamine 80 2 CF₃COOH N-(3,4-dichlorobenzyl)-N-(4-fluorophenyl)-4-353/355/357 piperidinamine 81 2 HCl, 1 H₂ON-(4-fluorophenyl)-N-(4-methylbenzyl)-4- 299 piperidinamine 82 2 CF₃COOHN-(4-fluorophenyl)-N-(4-methylbenzyl)-4- 299 piperidinamine 83 2 HCl,0.5 H₂O N-(4-fluorophenyl)-N-[4-(trifluoromethyl)benzyl]-4- 353piperidinamine 84 2 HClN-(4-fluorophenyl)-N-[4-(trifluoromethyl)benzyl]-4- 353 piperidinamine85 N-(4-chlorophenyl)-N-(4-fluorobenzyl)-4- 319 piperidinamine 86 2CF₃COOH N-(3-chlorobenzyl)-N-(4-methylphenyl)-4- 315/317 piperidinamine87 2 CF₃COOH N-(3,4-difluorobenzyl)-N-(4-methylphenyl)-4- 317piperidinamine 88 2 CF₃COOH N-(4-fluorobenzyl)-N-(4-methylphenyl)-4- 299piperidinamine 89 2 CF₃COOH N-(4-chlorobenzyl)-N-(4-methylphenyl)-4-315/317 piperidinamine 90 2 CF₃COOHN-(3,4-dichlorobenzyl)-N-(4-methylphenyl)-4- 349/351/353 piperidinamine91 2 CF₃COOH N-(4-methylphenyl)-N-[4-(trifluoromethyl)benzyl]-4- 349piperidinamine 92 N-(4-fluorobenzyl)-N-[4-(trifluoromethyl)phenyl]-4-353 piperidinamine

EXAMPLE 2 Binding Assays 2.1 H1 Binding

Affinity of the test compounds for the human histamine H1 receptor wasevaluated by a [³H]-mepyramine binding assay. This binding was performedas described by Gillard et al. (Gillard M., Van der Perren C.,Moguilevsky N., Massingham R, Chatelain P., Mol. Pharmacol. (2002), 61,391-399).

2.2 5-HT Uptake

Affinity of the test compounds for the Serotonin Transporter wasevaluated by a [³H]-Paroxetine binding assay. This binding was performedas described by Marcusson et al. (Marcusson J. O., Bergstrom M.,Eriksson K., Ross S. B., J. Neurochem. (1988), 50, 1783) with slightmodifications. Membrane proteins (100-200 μ) from rat cerebral cortexwere incubated for 120 min at 25° C. in 2 ml of a 50 mM Tis-HCl (pH 7.4)buffer containing 2 mM MgC12 and 0.05 nM radioligand. Non specificbinding defined as the residual binding was measured in the presence of5 μM Imipramine.

2.3 5-HT2 Binding

The affinity of the test compounds for the 5-HT2 receptors was evaluatedby a [³H]-Ketanserine binding assay. This binding was performedaccording to Leysen et al. (Leysen J. E., Niemegeers C. J., Van NuetenJ. M., Laduron P. M., Mol. Pharmacol. (1982), 21, 301-314) with slightmodifications. Briefly, 250 μg of membrane proteins from rat cerebralcortex were incubated for 60 min at 25° C. in 1 ml of a 50 mM Tris-HCl(pH 7.4) buffer containing 2 mM MgCl₂ and 0.2 nM radioligand. Nonspecific binding was defined as the residual binding measured in thepresence of 1 μM Chlorpromazine.

1. A 4-aminopiperidine compound of formula I or a pharmaceuticallyacceptable salt thereof,

wherein R¹, R², R³, R⁴ independently are selected from hydrogen,fluorine, chlorine, methyl and trifluoromethyl, with the proviso that,if R¹ R² and R⁴ are hydrogen, then R³ is not hydrogen, fluorine, orchlorine.
 2. A 4-aminopiperidine compound according to claim 1 whereinR² is hydrogen, fluorine or methyl, and R⁴is hydrogen, fluorine,chlorine or trifluoromethyl.
 3. A 4-aminopiperidine compound accordingto claim 1 wherein R¹ is hydrogen, fluorine or chlorine; R² is hydrogen,fluorine or methyl; R³ is hydrogen, fluorine, chlorine or methyl; and R⁴is hydrogen, fluorine or chlorine.
 4. A 4-aminopiperidine compoundaccording to claim 1 wherein R¹ is hydrogen or fluorine; R² is hydrogenor fluorine; R³ is fluorine or methyl: and R⁴ is hydrogen.
 5. A4-aminopiperidine compound according to claim 1 selected from the groupconsisting of N-(4-methylbenzyl)-N-phenyl -4-piperidinamine;N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine; N-(3-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine;N-(4-fluorobenzyl)-N-(4-fluorophenyl)-4-piperidinamine;N-(4-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine; or apharmaceutically acceptable salt thereof. 6.N-(4-fluorobenzyl)-N-(3-fluorophenyl)-4-piperidinamine or apharmaceutically acceptable salt thereof.
 7. N-(3-fluorophenyl)-N-(4-methylbenzyl)-4-piperidinamine or a pharmaceuticallyacceptable salt thereof.
 8. A pharmaceutical composition comprising asactive ingredient a therapeutically effective amount of a compoundaccording to claim 1 and a pharmaceutically acceptable adjuvant, diluentor carrier.
 9. A compound of formula II,

wherein R¹, R², R³, R⁴independently are selected from hydrogen,fluorine, chlorine, methyl and trifluoromethyl with the proviso that, ifR¹, R² and R⁴are hydrogen, then R³ is not hydrogen, fluorine, orchlorine; and P is,-methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl,9-(2-sulfo)fluorenylmethoxycarbonyl,9-(2,7-dibromo)fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2-phenylethoxycarbonyl, 2-chloroethoxycarbonyl, benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, benzenesulfenyl, 2-nitrobenzenesulfenyl,tosyl, benzenesulfonyl, methyl, tert-butyl, allyl, benzyl,bis(4-methoxyphenyl)methyl or 2,4-dinitrophenyl.
 10. The compoundaccording to claim 9 selected from the group consisting of tert-butyl4-[3-fluoro(4-fluorobenzyI]anilino]-1-piperidinecarboxylate; tert-butyl4-{[3-(trifluoromethyl)benzyl]aniline}-1-piperidinecarboxylate;tert-butyl 4-{(3-chlorobenzyl)aniline]-1-pipendinecarboxylate;tert-butyl 4-[(3,4-difluorobenzyl)aniline]-1-piperidinecarboxylate;tert-butyl 4-[(3,4-dichlorobenzyl)anilinoI]-1-piperidinecarboxylate;tert-butyl 4-[(3,4-methylbenzyl)anilino)-1-piperidinecarboxylate;tert-butyl 4-{[4-(trifluoromethyl)benzyl]aniline}-1-piperidinecarboxylate; tert-butyl 4-[(3,4-difluorobenzyl)-3-fluoroanilino]-1-piperidinecarboxyiate; tert-butyl4-[(4-chlorobenzyl)-3-fluoroanilino]-1-piperidinecarboxylate; tert-butyl4-[(3 ,4-dichlorobenzyl)-3-fluoroanilino]- 1-piperidinecarboxylate;tert-butyl 4-{3 -fluoro(4-methylbenzyl)anilno]-1-piperidinecarboxylate;tert-butyl 4-{3-fluoro [4(trifluoromethyl)benzyl]aniline}-1-piperidinecarboxylate; tert-butyl4-[(3-chlorobenzyl)-3-methylanilino]-1-piperidinecarboxylate; tert-butyl4-[(3 ,4-difluorobenzyl)-3-methylanilino]- 1-piperidinecarboxylate;tert-butyl 4-[(4-fluorobenzyl)-3-methylanilino]-1-piperidinecarboxylate;tert-butyl 4-[(4-chlorobenzyl)-3-methylanilino]-1-piperidinecarboxylate; tert-butyl 4-[(3,4-dichlorobenzyl)-3-methylanilino]-1-piperidinecarboxylate; tert-butyl4-(3-methy[4-(trifluoromethyl)benzyl]aniline)-1-piperidinecarboxylate;tert-butyl 4-(benzyl-4-fluoroanilino)-1-piperidinecarboxylate;tert-butyl 4-{4-fluoro [3(trifluoromethyl)benzyl]aniline }-1-piperidinecarboxylate; tert-butyl 4-[(3-chlorobenzyl)-4-fluoroanilino]-1-piperidinecarboxylate; tert-butyl4-[(3 ,4-difluorobenzyl)-4-fluoroanilino]-1-piperidinecarboxylate;tert-butyl 4-[4-fluoro(4-fluorobenzyl)aniline]-1-piperidinecarboxylate;tert-butyl 4-[(4-chlorobenzyl)-4-fluoroanilino]-1-piperidinecarboxylate;tert-butyl 4-[(3,4-dichlorobenzyl)-4-fluoroanilino]-1-piperidinecarboxylate; tert-butyl4-[4-fluoro(4-methylbenzyl)aniline]-1-piperidinecarboxylate; tert-butyl4-{4-fluoro [4-(trifluoromethyl)benzyl]anilino]-1-piperidinecarboxylate;tert-butyl 4- [4-chloro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate;tert-butyl 4-[(3-chlorobenzyl)-4-methylanilino]-1-piperidinecarboxylate;tert-butyl 4-[(3,4difluorobenzyl)-4-methlyanilino]-1-piperidinecarboxylate; tert-butyl4-[(4-fluorobenzyl)-4-methylanilino]-1-piperidinecarboxylate; tert-butyl4-[(4-chlorobenzyl)-4-methylanilino]-1-piperidinecarboxylate; tert-butyl4-[(3 ,4-dichlorobenzyl)-4-methylanilino]-1-piperidinecarboxylate;tert-butyl{4[4-methyl(4-trifluoromethyl)benzyl]aniline}-1-piperidinecarboxylate;tert-butyl4-[(4-fluorobenzyl)-4-(trifluoromethyl)aniline]-1-piperidinecarboxylate;and tert-butyl4-[(3-chlorobenzyl)-3-fluoroanilino]-1-piperidinecarboxylate.